This invention relates to novel indole compounds useful for Inflammatory Diseases.
The structure and physical properties of human non-pancreatic secretory phospholipase A2 (hereinafter called, xe2x80x9csPLA2xe2x80x9d) has been thoroughly described in two articles, namely, xe2x80x9cCloning and Recombinant Expression of Phospholipase A2 Present in Rheumatoid Arthritic Synovial Fluidxe2x80x9d by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5335-5338, 1989; and xe2x80x9cStructure and Properties of a Human Non-pancreatic Phospholipase A2xe2x80x9d by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference.
It is believed that sPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit sPLA2 mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of sPLA2; such as sepsis or rheumatoid arthritis.
It is desirable to develop new compounds and treatments for sPLA2 induced diseases.
This invention provides novel indole compounds having potent and selective effectiveness as inhibitors of mammalian sPLA2.
This invention is also the use of novel indole compounds useful in the treatment and prevention of Inflammatory Diseases.
This invention is also the use of novel of indole compounds to inhibit mammalian sPLA2 mediated release of fatty acids.
This invention is also a pharmaceutical composition containing any of the indole compounds of the invention.
I. Definitions:
The term, xe2x80x9cInflammatory Diseasesxe2x80x9d refers to diseases such as inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosing spondylitis, Reiter""s syndrome, psoriatic arthropathy, enterapathric spondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis, Reactive arthropathy, infectious or post-infectious arthritis, gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with xe2x80x9cvasculitic syndromesxe2x80x9d, polyarteritis nodosa, hypersensitivity vasculitis, Luegenec""s granulomatosis, polymyalgin rheumatica, joint cell arteritis, calcium crystal deposition arthropathris, pseudo gout, non-articular rheumatism, bursitis, tenosynomitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), miscellaneous forms of arthritis, neuropathic joint disease (charco and joint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathries, hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat""s Disease, systemic lupus erythrematosis, or relapsing polychondritis and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit sPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products.
The term, xe2x80x9cindole nucleusxe2x80x9d refers to a nucleus (having numbered positions) with the structural formula (X): 
The indole compounds of the invention employ ertain defining terms as follows:
The term, xe2x80x9calkylxe2x80x9d by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, sec-butyl, n-pentyl, and n-hexyl.
The term, xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms means a straight chain or branched monovalent hydrocarbon group having the stated number range of carbon atoms, and typified by groups such as vinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers.
The term, xe2x80x9chydrocarbylxe2x80x9d, means an organic group containing only carbon and hydrogen.
The term, xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo, or iodo. The term, heterocyclic radical, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic. nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyrrolyl, pyrrolodinyl, piperidinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, riazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl, dipyridylyl. phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl,morpholino, thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrahydrothiopheneyl, pentamethylenesulfadyl, 1,3-dithianyl, 1,4-dithianyl, 1,4-thioxanyl, azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl and quinoxalinyl.
The term, xe2x80x9ccarbocyclic radicalxe2x80x9d refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms. Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, spiro[5.5]undecanyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a): 
where n is a number fromn 1 to 8.
The term, xe2x80x9cnon-interfering substituentxe2x80x9d, refers to radicals suitable for substitution at positions 4,5,6 and/or 7 of the indole nucleus and on other nucleus substituents (as hereinafter described for Formula I), and radicals suitable for substitution on the heterocyclic radical and carbocyclic radical as defined above. Illustrative non-interfering radicals are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C1-C8 alkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C2-C8 haloalkoxy, C1-C8 haloalkylsulfonyl, C2-C8 haloalkyl, C1-C8 hydroxyalkyl, xe2x80x94C(O)O(C1-C8 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C8 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2R), xe2x80x94CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nxe2x80x94CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, and carbonyl; where n is from 1 to 8 and R is C1-C8 alkyl.
The term, xe2x80x9corganic substituentxe2x80x9d refers to a monovalent radical consisting of carbon and hydrogen with or without oxygen, nitrogen, sulfur, halogen, or other elements. Illustrative organic substituents are C1-C8 alkyl, aryl, C7-C14 aralkyl, C7-C14 alkaryl, C3-C8 cycloalkyl, C1-C8 alkoxyalkyl and these groups substitued with halogen, xe2x80x94CF3, xe2x80x94OH, C1-C8 alkyl, amino, carbonyl, and xe2x80x94CN.
The term, xe2x80x9cacylamino acid groupxe2x80x9d is represented by the formula: 
wherein R4a is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl and aryl, xe2x80x94CF3; and wherein NR4b is an amino acid residue of either a natural or unnatural amino acid with the nitrogen atom being part of the amino group of the amino acid. A typical amino acid is selected from the group comprising isoleucine, valine, phenylalanine, aspartic acid, leucine, glycine, asparagine, cystein, glutamine, glutamic acid, histidine, lysine, methionine, serine, threonine, tryptophan, tyrosine and derivatives thereof. Also contemplated within the definition of amino acid is l-proline, d-proline and derivatives thereof. Also contemplated within the definition of amino acids are peptides, polypeptides and derivatives thereof.
The term xe2x80x9csubstituted groupxe2x80x9d is an organic group substituted with one or more non-interfering substituents.
The terms, xe2x80x9camino acid residuexe2x80x9d refer to the portion of the amino acid group coupled at the nitrogen atom of the amino terminus. It is the amino acid less a hydrogen atom from the amino terminus. It is further illustrated as used herein for the amino acid alanine attached at the nitrogen atom as shown below: 
The words, xe2x80x9cacylamino acid linkerxe2x80x9d refer to a divalent linking group symbolized as, xe2x80x94(Lc)xe2x80x94, which has the function of joining the 4-position of the indole nucleus to an acylamino acid group in the general relationship: 
The words, xe2x80x9cacylamino acid linker lengthxe2x80x9d, refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group xe2x80x94(Lc)xe2x80x94 that connects the 4-position of the indole nucleus with the acylamino acid group. The presence of a carbocyclic ring in xe2x80x94(Lc)xe2x80x94 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene or cyclohexane ring in the acid linker counts as 2 atoms in calculating the length of xe2x80x94(Lc)xe2x80x94. Illustrative acylamino acid linker groups are; 
wherein, groups (a), (b) and (c) have acid linker lengths of 5, 7, and 2, respectively.
The term, xe2x80x9c(acidic group)xe2x80x9d means an organic group which when attached to an indole nucleus at position 5, through suitable linking atoms (hereinafter defined as the xe2x80x9cacid linkerxe2x80x9d), acts as a proton donor capable of hydrogen bonding. Illustrative of an (acidic group) are the following:
-5-tetrazolyl,
xe2x80x94SO3H, 
where n is 1 to 8, R80 is a metal or C1-C8 and R81 is an organic substituent or xe2x80x94CF3.
The words, xe2x80x9cacid linkerxe2x80x9d refer to a divalent linking group symbolized as, xe2x80x94(La)xe2x80x94, which has the function of joining the 5 position of the indole nucleus to an acidic group in the general relationship: 
The words, xe2x80x9cacid linker lengthxe2x80x9d, refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group xe2x80x94(La)xe2x80x94 that connects the 5 position of the indole nucleus with the acidic group. The presence of a carbocyclic ring in xe2x80x94(La)xe2x80x94 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene or cyclohexane ring in the acid linker counts as 2 atoms in calculating the length of xe2x80x94(La)xe2x80x94. Illustrative acid linker groups are; 
wherein, groups (a), (b), and (c) have acid linker lengths of 5, 7, and 2, respectively.
The term, xe2x80x9caminexe2x80x9d, includes primary, secondary and tertiary amines.
The terms, xe2x80x9cmammalxe2x80x9d and xe2x80x9cmammalianxe2x80x9d include human and domesticated quadrupeds.
The term, xe2x80x9calkylene chain of 1 or 2 carbon atomsxe2x80x9d refers to the divalent radicals, xe2x80x94CH2xe2x80x94CH2xe2x80x94 and xe2x80x94CH2xe2x80x94.
The term, xe2x80x9cgroup containing 1 to 4 non-hydrogen atomsxe2x80x9d refers to relatively small groups which form substituents at the 2 position of the indole nucleus, said groups may contain non-hydrogen atoms alone, or non-hydrogen atoms plus hydrogen atoms as required to satisfy the unsubstituted valence of the non-hydrogen atoms, for example; (i) groups absent hydrogen which contain no more than 4 non-hydrogen atoms such as xe2x80x94CF3, xe2x80x94Cl, xe2x80x94Br, xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO3; and (ii) groups having hydrogen atoms which contain less than 4 non-hydrogen atoms such as xe2x80x94CH3, xe2x80x94C2H5, and xe2x80x94CHxe2x95x90CH2.
The term xe2x80x9coxime amidexe2x80x9d means the radical, xe2x80x94Cxe2x95x90NORxe2x80x94C(O)NH2 
The term xe2x80x9cthio-oxime amidexe2x80x9d means the radical xe2x80x94Cxe2x95x90NORxe2x80x94C(S)xe2x80x94NH2.
The term xe2x80x9cspiro[5.5]undecanylxe2x80x9d refers to the group represented by the formula; 
II. The amino acid 1H-indole Compounds of the Invention:
The present invention provides novel classes of indole compounds useful as sPLA2 inhibitors for the treatment of inflammation. Classes of indole compounds of this invention include indole glyoxylamide amino acid derivatives, indole-3-oxime amide amino acid derivatives and indole acetamide amino acid derivatives. The compounds of the invention have the general formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof; 
wherein;
R1 is selected from groups (a), (b), and (c) wherein;
(a) is C7-C20 alkyl, C7-C20 haloalkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or
(c) is the group xe2x80x94(L1)xe2x80x94R11; where, xe2x80x94(L1)xe2x80x94 is a divalent linking group of 1 to 8 atoms and where R11 is a group selected from (a) or (b);
R2 is hydrogen, or a group containing 1 to 4 non-hydrogen atoms plus any required hydrogen atoms;
R3 is xe2x80x94(L3)xe2x80x94 Z, where xe2x80x94(L3)xe2x80x94 is a divalent linker group selected from a bond or a divalent group selected from: 
and Z is selected from an oxime amide or oxime thioamide group represented by the formulae, 
wherein X is oxygen or sulfur, Ra is independently selected from hydrogen, C1-C8 alkyl, aryl, C1-C8 alkaryl, C1-C8 alkoxy, aralkyl and xe2x80x94CN;
R4 is the group, xe2x80x94(Lc)xe2x80x94(acylamino acid group); wherein xe2x80x94(Lc)xe2x80x94, is an acylamino acid linker having an acylamino acid linker length of 1 to 8;
R5 is selected from hydrogen, a non-interfering substituent, or the group, xe2x80x94(La)xe2x80x94(acidic group); wherein xe2x80x94(La)xe2x80x94, is an acid linker having an acid linker length of 1 to 8.
R6 and R7 are selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituent(s), heterocyclic radicals, and heterocyclic radical substituted with non-interfering substituent(s).
A preferred subclass of compounds of formula (I) are those where for R1 the divalent linking group xe2x80x94(L1)xe2x80x94 is a group represented by any one of the following formulae (Ia), (Ib), (Ic), (Id), (Ie), or (If): 
where Q1 is a bond or any of the divalent groups (Ia), (Ib), (Ic), (Id), (Ie), and (If) and each R10 is independently hydrogen, C1-8 alkyl, C1-8 haloalkyl or C1-8 alkoxy.
Particularly preferred as the linking group xe2x80x94(L1)xe2x80x94 of R1 is an alkylene chain of 1 or 2 carbon atoms, namely, xe2x80x94(CH2)xe2x80x94 or xe2x80x94(CH2xe2x80x94CH2)xe2x80x94.
The preferred group for R11 is a substituted or unsubstituted group selected from the group consisting of C5-C14 cycloalkyl, C5-C14 cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a); 
where n is a number from 1 to 8.
Particularly preferred are compounds wherein for R1 the combined group xe2x80x94(L1)xe2x80x94R11 is selected from the group consisting of 
where R12 is a radical independently selected from halo, C1-8 alkyl, C1-C8 alkoxy, xe2x80x94Sxe2x80x94(C1-C8 alkyl), xe2x80x94Oxe2x80x94(C1-C8 alkyl) and C1-C8 haloalkyl where t is a number from 0 to 5 and u is a number from 0 to 4 is the group xe2x80x94(L1)xe2x80x94R11; where, xe2x80x94(L1)xe2x80x94 is a divalent linking group of 1 to 8 atoms and where R11 is a group selected from (a) or (b).
Preferred for R11 is xe2x80x94(CH2)m-R12 wherein m is an integer from 1 to 6, and R12 is (d) a group represented by the formula: 
wherein a, c, e, n, q, and t are independently an integer from 0 to 2, R13 and R14 are independently selected from a halogen, C1 to C8 alkyl, C1 to C8 alkyloxy, C1 to C8 alkylthio, aryl, heteroaryl, and C1 to C8 haloalkyl, xcex1 is an oxygen atom or a sulfur atom, L5 is a bond, xe2x80x94(CH2)v-, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94CCxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94, v is an integer from 0 to 2, xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94, xcex3 is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C8 alkyloxy, C1 to C8 haloalkyloxy, C1 to C8 haloalkyl, aryl, and a halogen.
R2 is preferably selected from the group consisting of hydrogen, C1-C4 alkyl, C2-C4 alkenyl, xe2x80x94Oxe2x80x94(C1-C3 alkyl), xe2x80x94Sxe2x80x94(C1-C3 alkyl), xe2x80x94C3-C4 cycloalkyl xe2x80x94CF3, halo, xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO3. Particularly preferred R2 groups are selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, xe2x80x94F, xe2x80x94CF3, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94Oxe2x80x94CH3.
A preferred subclass of compounds of formula (I) are those wherein X is oxygen.
Another preferred subclass of compounds of formula (I) are those wherein Z is an oxime amide group. 
Also preferred are compounds of formula (I) wherein R3 is an oxime amide group and Ra is hydrogen, methyl or ethyl. For the group R3 it is preferred that the linking group xe2x80x94(L3)xe2x80x94 be a bond.
Another preferred subclass of compounds of formula (I) are those wherein R4 is a substituent having an acylamino acid linker with an acylamino acid linker length of 2 or 3 and the acylamino acid linker group, xe2x80x94(Lc)xe2x80x94, for R4 is selected from a group represented by the formula; 
where Q2 is selected from the group xe2x80x94(CH2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94C(O)xe2x80x94, and xe2x80x94Sxe2x80x94, and each R40 is independently selected from hydrogen, C1-C8 alkyl, aryl, C1-C8 alkaryl, C1-C8 alkoxy, aralkyl, and halo. Most preferred are compounds where the acylamino acid linker, xe2x80x94(Lc)xe2x80x94, for R4 is selected from the specific groups; 
where R40 is hydrogen or C1-C8 alkyl. Preferred as the (acylamino acid group) in the group R4 is the group: 
wherein R4a is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl and aryl; and wherein NR4b is an amino acid residue of either a natural or unnatural amino acid with the nitrogen atom being part of the amino group of the amino acid. A preferred R4a group is the group hydrogen (H). A preferred source of amino acid residue is the amino acid group selected from the group comprising isoleucine, valine, phenylalanine, aspartic acid, leucine, glycine and isomers and derivatives thereof. A salt or a prodrug derivative of the (acylamino acid group) is also a suitable substituent.
Particularly preferred are R4b groups that combine with the nitrogen atom to represent amino acid residues from the amino acid groups selected from: glycine, glycine methyl ester, L-alaninie, L-alanine methylester,L-leucine, L-leucine methyl ester, L-aspartic acid, L-aspartic acid dimethyl ester, L-phenyl alanine, L-phenylalanine methyl ester, malonic acid, malonic acid dimethylester, L-valine, L-valine methyl ester, L-isoleucine, L-isoleucine methyl ester, or salt, and derivatives thereof.
Preferred acid linker, xe2x80x94(La)xe2x80x94, for R5 is selected from the group consisting of; 
wherein R54, R55, R56 and R57 are each independently hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, or halo. Preferred (acidic group) for R5 is selected from the group consisting of xe2x80x94CO2H, xe2x80x94SO3H and xe2x80x94P(O)(OH)2.
Another preferred subclass of compounds of formula (I) are those wherein for R6 and R7 the non-interfering substituent is independently methyl, ethyl, propyl, isopropyl, thiomethyl, xe2x80x94O-methyl, C4-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, xe2x80x94C(O)O(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2R), xe2x80x94CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nxe2x80x94CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, and carbonyl; where n is from 1 to 8.
Most preferred as non-interfering substituents are methyl, ethyl, propyl, and isopropyl.
Preferred compounds of the invention are those having the general formula (II), or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; 
wherein;
R22 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, xe2x80x94F, xe2x80x94CF3, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94Oxe2x80x94CH3;
wherein R4a is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl and aryl; and wherein NR4b is an amino acid residue of either a natural or unnatural amino acid with the nitrogen atom being part of the amino group of the amino acid. A preferred R4a group is the group hydrogen (H); and xe2x80x94(L4)xe2x80x94 is a divalent group selected from; 
where R40, R41, R42, and R43 are each independently selected from hydrogen or C1-C8 alkyl.
R16 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio C1-C8 haloalkyl, C1-C8 hydroxyalkyl, and halo.
R13 is selected from hydrogen and C1-C8 alkyl, C1-C8 alkoxy, xe2x80x94Sxe2x80x94(C1-C8 alkyl), C1-C8 haloalkyl, C1-C8, phenyl, halophenyl, hydroxyalkyl, and halo, and t is an integer from 0 to 5.
Preferred specific compounds (and all pharmaceutically acceptable salts, solvates and prodrug derivatives thereof) which are illustrative of the compounds of the invention are as follow:
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]glycine;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]glycine methyl ester;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]glycine;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-alanine;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-alanine methyl ester;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-alanine;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-leucine;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-leucine methyl ester;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-leucine;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-aspartic acid;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-aspartic acid dimethyl ester;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-aspartic acid;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-phenylalanine;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-phenylalanine methyl ester;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-phenylalanine;
[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetamido]malonic acid;
[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetamido]malonic acid dimethyl ester;
[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetamido]malonic acid;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-valine;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-valine methyl ester;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-valine;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-isoleucine;
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-isoleucine methyl ester; and
N-[2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetyl]-L-isoleucine.
The salts of the above indole compounds represented by formulae (I) and (II) are an additional aspect of the invention. In those instances where the compounds of the invention possess acidic or basic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin.
Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound of the invention may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, bromide, chloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, malseate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate.
Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. Likewise, when the compounds contain an alkenyl or alkenylene group there exists the possibility of cis- and trans-isomeric forms of the compounds. The R- and S-isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans-isomers, are contemplated by this invention. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods. For example, a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic form into a mixture of diastereomers and diastereomers, because they have different melting points, different boiling points, and different solubilities can be separated by conventional means, such as crystallization.
Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly preferred esters as prodrugs are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl; tert-butyl, morpholinoethyl, and N,N-diethylglycolamido.
N,N-diethylglycolamido ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 2-chloro-N,N-diethylacetamide (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. 25,099-6).
Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3).
a) The 1H-indole-3-glyoxylamide amino derivative compounds of the invention are prepared by room temperature base catalyzed condensation of the amino acid protected at the acid terminus by protecting group known in the literature but preferably as the methyl ester with the 1H-indole-3-glyoxylamide acid derivative compound of formula (1) as shown in Scheme I: 
Typically, the condensation or coupling is performed in a solvent such a dimethyl formamide, tetrahydrofuran or aqueous mixtures of the like. In general protic solvents are preferred for the purpose of this invention. The reaction is catalyzed by a base including weak organic or inorganic bases. Organic bases such as collidine are preferred. The reaction is also preferably run in the presence of agents that retard or reduce racemization of the amino acid or its derivative, such as for example, benzotriazolyl-N-oxy-tris(dimethylamino)phosphonium hexafluorophosphate. Upon completion of the reaction, the mixture is concentrated in vacuo. The resulting product mixture is chromatographed to obtain the target compound.
One of skill in the art is aware that the derivatives of the acid such as the acid salt or the methyl ester of the acid, can be reacted with the amino acid or derivatives thereof to obtain the protected compound 2 or a corresponding derivative. Such methods are well known in the arts and can be found in reference texts such as for example J. March Advanced Organic Chemistry, Wiley Interscience publishers, New York, N.Y., 1985, and R. C. Larock Comprehensive Organic Transformations, VCH Publishers, New York, N.Y., 1989. The protected compounds of formula (2) are also useful sPLA2 inhibitors and are also compounds of this invention.
b) 1H-indole-3-acetamide amino acid derivative sPLA2 inhibitors are similarly prepared by condensation of the protected amino acid with the 1H-indole-3-acetamide sPLA2 inhibitor. The 1H-indole-3-acetamide sPLA2 inhibitors and methods of making them are set out in U.S. Pat. No. 5,684,034, the entire disclosure of which is incorporated herein by reference. Indole-3-acetamide amino acid derivative sPLA2 inhibitors of this invention are represented by compounds of formula (IIb), and pharmaceutically acceptable salts and prodrug derivatives thereof, 
wherein;
X is oxygen or sulfur;
R11 is selected from groups (i), (ii) (iii) and (iv) where;
(i) is C6-C20 alkyl, C6-C20 alkenyl, C6-C20 alkynyl, C6-C20 haloalkyl, C4-C12 cycloalkyl, or
(ii) is aryl or aryl substituted by halo, nitro, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OH, xe2x80x94SH, C1-C10 alkyl, C1-C10 alkylthio, C1-C10 alkoxyl, carboxyl, amino, or hydroxyamino; or
(iii) is xe2x80x94(CH2)nxe2x80x94(R80), or xe2x80x94(NH)xe2x80x94(R81), where n is 1 to 8, and R80 is a group recited in (i), and R81 is selected from a group recited in (i) or (ii);
(iv) is 
where R87 is hydrogen or C1-C10 alkyl, and R88 is selected from the group; phenyl, naphthyl, indenyl, and biphenyl, unsubstituted or substituted by halo, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OH, xe2x80x94SH, C1-C10 alkylthio, C1-C10 alkoxyl, phenyl, nitro, C1-C10 alkyl, C1-C10 haloalkyl, carboxyl, amino, hydroxyamino; or a substituted or unsubstituted 5 to 8 membered heterocyclic ring;
R12 is halo, C1-C2 alkylthio, C1-C2 alkyl, C1-C2 alkyaryl or C1-C2 alkoxy;
each R13 is independently hydrogen, halo, or methyl;
R14 is the group xe2x80x94Lcxe2x80x94[acylamino acid], wherein the acylamino acid group is xe2x80x94C(O)xe2x80x94NR14aR14b wherein R14a is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl; and xe2x80x94Lcxe2x80x94 is as defined supra, and wherein NR14b is an amino acid residue of either a natural or unnatural amino acid with the nitrogen atom being part of the amino group of the amino acid. Most preferred are compounds of formula II wherein the group R14a is a hydrogen atom (H). A preferred source of the amino acid residue NR14b is an amino acid selected from the group comprising isoleucine, valine, phenylalanine, aspartic acid, leucine, glycine and isomers and derivatives thereof;
R15 is selected from hydrogen, a non-interfering substituent, or the group, xe2x80x94(La)xe2x80x94 (acidic group); wherein xe2x80x94(La)xe2x80x94, is an acid linker having an acid linker length of 1 to 8;
R16 and R17 are each independently hydrogen, C1-C10 alkyl, C1-C10 alkenyl, C1-C10 alkynyl, C3-C8 cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl groups in the set R15, R16, and R17, combine with the ring carbon atoms to which they are attached to form a 5 or 6 membered substituted or unsubstituted carbocyclic ring; or C1-C10 haloalkyl, C1-C10 alkoxy, C1-C10 haloalkoxy, C4-C8 cycloalkoxy, phenoxy, halo, hydroxy, carboxyl, xe2x80x94SH, xe2x80x94CN, C1-C10 alkylthio, arylthio, thioacetal, xe2x80x94C(O)O(C1-C10 alkyl), hydrazide, hydrazino, hydrazido, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94NR82R83, and xe2x80x94C(O)NR82R83, where, R82 and R83 are independently hydrogen, C1-C10 alkyl, C1-C10 hydroxyalkyl, or taken together with N, R82 and R83 form a 5- to 8-membered heterocyclic ring; or a group having the formula; 
where,
R84 and R85 are each independently selected from hydrogen, C1-C10 alkyl, hydroxy, or R84 and R85 taken together are xe2x95x90O;
p is 1 to 5,
Z is a bond, xe2x80x94Oxe2x80x94, xe2x80x94N(C1-C10 alkyl)xe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94Sxe2x80x94; and
Q is xe2x80x94CON(R82R83), -5-tetrazolyl, xe2x80x94SO3H, 
where n is 1 to 8, R86 is independently selected from hydrogen, a metal, or C1-C10 alkyl, and R99 is selected from hydrogen or C1-C10 alkyl.
c) Indole-3-Oxime amide compounds of the invention are represented by compounds of formula (III) or a pharmaceutically acceptable salt, solvate or prodrug thereof; 
wherein
R1 is selected from groups (a), (b), and (c) wherein;
(a) is C7-C20 alkyl, C7-C20 haloalkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or
(c) is the group xe2x80x94(L1)xe2x80x94R11; where, xe2x80x94(L1)xe2x80x94 is a divalent linking group of 1 to 8 atoms and where R11 is a group selected from (a) or (b).
Particularly preferred are compounds wherein for R1 the combined group xe2x80x94(L1)xe2x80x94R11 is selected from the group consisting of 
where R12 is a radical independently selected from halo, C1-C8 alkyl, C1-C8 alkoxy, xe2x80x94Sxe2x80x94(C1-C8 alkyl), xe2x80x94Oxe2x80x94(C1-C8 alkyl) and C1-C8 haloalkyl where t is a number from 0 to 5 and u is a number from 0 to 4.
Also preferred for R11 is xe2x80x94(CH2)m-R12 wherein m is an integer from 1 to 6, and R12 is (d) a group represented by the formula: 
wherein a, c, e, n, q, and t are independently an integer from 0 to 2, R13 and R14 are independently selected from a halogen, C1 to C8 alkyl, C1 to C8 alkyloxy, C1 to C8 alkylthio, aryl, heteroaryl, and C1 to C8 haloalkyl, xcex1 is an oxygen atom or a sulfur atom, L5 is a bond, xe2x80x94(CH2)v-, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94CCxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94, v is an integer from 0 to 2, xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94, xcex3 is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C8 alkyloxy, C1 to C8 haloalkyloxy, C1 to C8 haloalkyl, aryl, and a halogen.
R2 is hydrogen, or a group containing 1 to 4 non-hydrogen atoms plus any required hydrogen atoms;
xe2x80x94(L3)xe2x80x94 Z, is the group where xe2x80x94(L3)xe2x80x94 is a divalent linker group selected from a bond or a divalent group selected from: 
xe2x80x83and Z is selected from an oxime amide or oxime thioamide group represented by the formulae, 
wherein, X is oxygen or sulfur; and Ra is selected from hydrogen, C1-C8 alkyl, aryl, C1-C8 alkaryl, C1-C8 alkoxy, aralkyl and xe2x80x94CN;
R4 is the group, xe2x80x94(Lc)xe2x80x94(acylamino acid group); wherein xe2x80x94(Lc)xe2x80x94, is an acylamino acid linker having an acylamino acid linker length of 1 to 8;
R5 is selected from hydrogen, a non-interfering substituent, or the group, xe2x80x94(La)xe2x80x94(acidic group); wherein
xe2x80x94(La)xe2x80x94, is an acid linker having an acid linker length of 1 to 8
R6 and R7 are selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituent(s), heterocyclic radicals, and heterocyclic radical substituted with non-interfering substituent(s).
A preferred subclass of compounds of formula (III) are those where for R1 the divalent linking group xe2x80x94(L1)xe2x80x94 is a group represented by any one of the following formulae (Ia), (Ib), (Ic), (Id), (Ie), or (If): 
where Q1 is a bond or any of the divalent groups (Ia), (Ib), (Ic), (Id), (Ie), and (If) and each R10 is independently hydrogen, C1-8 alkyl, C1-8 haloalkyl or C1-8 alkoxy.
Particularly preferred as the linking group xe2x80x94(L1)xe2x80x94 of R1 is an alkylene chain of 1 or 2 carbon atoms, namely, xe2x80x94(CH2)xe2x80x94 or xe2x80x94(CH2xe2x80x94CH2)xe2x80x94.
The preferred group for R11 is a substituted or unsubstituted group selected from the group consisting of C5-C14 cycloalkyl, C5-C14 cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a); 
where n is a number from 1 to 8.
Particularly preferred are compounds wherein for R1 the combined group xe2x80x94(L1)xe2x80x94R11 is selected from the group consisting of 
where R12 is a radical independently selected from halo, C1-C8 alkyl, C1-C8 alkoxy, xe2x80x94Sxe2x80x94(C1-C8 alkyl), xe2x80x94Oxe2x80x94(C1-C8 alkyl) and C1-C8 haloalkyl where t is a number from 0 to 5 and u is a number from 0 to 4.
Also preferred for R11 is xe2x80x94(CH2)m-R12 wherein m is an integer from 1 to 6, and R12 is (d) a group represented by the formula: 
wherein a, c, e, n, q, and t are independently an integer from 0 to 2, R13 and R14 are independently selected from a halogen, C1 to C8 alkyl, C1 to C8 alkyloxy, C1 to C8 alkylthio, aryl, heteroaryl, and C1 to C8 haloalkyl, xcex1 is an oxygen atom or a sulfur atom, L5 is a bond, xe2x80x94(CH2)v-, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94CCxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94, v is an integer from 0 to 2, xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94, xcex3 is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C8 alkyloxy, C1 to C8 haloalkyloxy, C1 to C8 haloalkyl, aryl, and a halogen.
R2 is preferably selected from the group consisting of hydrogen, C1-C4 alkyl, C2-C4 alkenyl, xe2x80x94Oxe2x80x94(C1-C3 alkyl), xe2x80x94Sxe2x80x94(C1-C3 alkyl), xe2x80x94C3-C4 cycloalkyl xe2x80x94CF3, halo, xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO3. Particularly preferred R2 groups are selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, xe2x80x94F, xe2x80x94CF3, xe2x80x94Cl, xe2x80x94Br, or xe2x80x940xe2x80x94CH3.
Another preferred subclass of compounds of formula (III) are those wherein R4 is a substituent having an acylamino acid linker with an acylamino acid linker length of 2 or 3 and the acylamino acid linker group, xe2x80x94(Lc)xe2x80x94, for R4 is selected from a group represented by the formula; 
where Q2 is selected from the group xe2x80x94(CH2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94C(O)xe2x80x94, and xe2x80x94Sxe2x80x94, and each R40 is independently selected from hydrogen, C1-C8 alkyl, aryl, C1-C8 alkaryl, C1-C8 alkoxy, aralkyl, and halo. Most preferred are compounds where the acylamino acid linker, xe2x80x94(Lc)xe2x80x94, for R4 is selected from the specific groups; 
where R40 is hydrogen or C1-C8 alkyl. Preferred as the (acylamino acid group) in the group R4 is the group: 
wherein R4a is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl and aryl; and wherein NR4b is an amino acid residue of either a natural or unnatural amino acid with the nitrogen atom being part of the amino group of the amino acid. A preferred R4a group is the group hydrogen (H). A preferred source of amino acid residue is the amino acid group selected from. the group comprising isoleucine, valine, phenylalanine, aspartic acid, leucine, glycine and isomers and derivatives thereof.
A salt or a prodrug derivative of the (acylamino acid group) is also a suitable substituent.
Particularly preferred are R4b groups that combine with the nitrogen atom to represent amino acid groups selected from: glycine, glycine methyl ester, L-alaninie, L-alanine methylester,L-leucine, L-leucine methyl ester, L-aspartic acid, L-aspartic acid dimethyl ester, L-phenyl alanine, L-phenylalanine methyl ester, malonic acid, malonic acid dimethylester, L-valine, L-valine methyl ester, L-isoleucine, L-isoleucine methyl ester, or salt, and derivatives thereof.
Preferred acid linker, xe2x80x94(La)xe2x80x94, for R5 is selected from the group consisting of; 
wherein R54, R55, R56 and R57 are each independently hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, or halo. Preferred (acidic group) for R5 is selected from the group consisting of xe2x80x94CO2H, xe2x80x94SO3H and xe2x80x94P(O)(OH)2 
Another preferred subclass of compounds of formula (III) are those wherein for R6 and R7 the non-interfering substituent is independently methyl, ethyl, propyl, isopropyl, thiomethyl, xe2x80x94O-methyl, C4-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, xe2x80x94C(O)O(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2R), xe2x80x94CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nxe2x80x94CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino; hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, and carbonyl; where n is from 1 to 8.
Most preferred as non-interfering substituents are methyl, ethyl, propyl, and isopropyl.
The indole-3-oxime compounds of the invention can be prepared following protocol of scheme 2 below; 
To introduce the oxime functionality, the methyl ester of the glyoxylamide (compound 10 in scheme 1, compound 1 in scheme 2, supra.) is heated with hydroxylamine hydrochloride (when R is H) in a THF/methanol mixture for 8 hours or until the reaction was deemed complete. The reaction product is isolated by chromatography or other known laboratory procedure to afford a white solid. Substituted oximes such as when R is methyl, ethyl, phenyl or other substituent can be prepared by reacting the corresponding substituted hydroxylamine hydrochloride or free base with the glyoxylamide as described supra. The ester functionality at the 4 or 5 position on the indole nucleus, as in for example, compound 2, can be: (a) converted to the acid by hydrolysis using lithium hydroxide or other known ester hydrolysis methods to afford compounds of formula 3, or (b) converted to an amide functionality directly or via the acid functionality to afford compounds of formula 4. General procedures for the conversion of organic acids to amino acid are well known to artisans in the field, and have been documented in general reference texts including, for example, J. March Advanced Organic Chemistry, Wiley Interscience publishers, New York, N,Y., 1985, and R. C. Larock Comprehensive Organic Transformations, VCH Publishers, New York, N,Y., 1989.
The oxime acid compounds of formula 3 such as the methyloxime compound such as that of formula 4 can be converted to the corresponding amino acid derivative via the methylester by coupling with various amino acids by general coupling procedures known to one skilled in the art. Additional references, or procedures are found in J. March Advanced Organic Chemistry, Wiley Interscience publishers, New York, N,Y., 1985; R. C. Larock Comprehensive Organic Transformations, VCH Publishers, New York, N,Y., 1989 and J. Jones Amino Acids and Peptide Synthesis, Oxford Science Publications, Stephen G. Davis, Editor, Oxford University Press Inc., New York, N.Y., 1992.
III. Method of Making the 1H-Indole-3-Glyoxylamide Starting Material for Preparing the Compounds of the Invention:
The synthesis of the indole compounds of the invention (viz., Compounds of Formulae I and II) can be accomplished by well known methods as recorded in the chemical literature. In particular, the indole starting materials may be prepared by the synthesis schemes taught in U.S. Pat. No. 5,654,326; the disclosure of which is incorporated herein by reference. Another method of making 1H-indole-3-glyoxylamide sPLA2 inhibitors is described in U.S. patent application Ser. No. 09/105381, filed Jun. 26, 1998 and titled, xe2x80x9cProcess for Preparing 4-substituted 1-H-Indole-3-glyoxyamidesxe2x80x9d the entire disclosure of which is incorporated herein by reference.
U.S. patent application Ser. No. 09/105381 discloses the following process having steps (a) thru (i)
Preparing a compound of the formula (Iz) or a pharmaceutically acceptable salt or prodrug derivative thereof 
wherein:
R1z is selected from the group consisting of xe2x80x94C7-C20 alkyl, 
where
R10Z is selected from the group consisting of halo, C1-C10 alkyl, C1-C10 alkoxy, xe2x80x94Sxe2x80x94(C1-C10 alkyl) and halo(C1-C10 alkyl, and tz is an integer from 0 to 5 both inclusive;
R2z is selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, xe2x80x94Oxe2x80x94(C1-C2 alkyl), xe2x80x94Sxe2x80x94(C1-C2 alkyl), aryl, aryloxy and HET;
R4z is the group xe2x80x94CO2H, or salt and prodrug derivative thereof; and
R5z, R6z and R7z are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, halo(C2-C6)alkyl, bromo, chloro, fluoro, iodo and aryl;
which process comprises the steps of:
a) halogenating a compound of formula Xz 
where R8Z is (C1-C6)alkyl, aryl or HET;
with SO2Cl2 to form a compound of formula IX 
b) hydrolyzing and decarboxylating a compound of formula IXz 
to form a compound of formula VIIIz 
c) alkylating a compound of formula VIIz 
with a compound of formula VIIIz 
to form a compound of formula VIz 
d) aminating and dehydrating a compound of formula VIz 
with an amine of the formula R1zNH2 in the presence of a solvent that forms and azeotrope with water to form a compound of formula Vz;
e) oxidizing a compound of formula Vz 
by refluxing in a polar hydrocarbon solvent having a boiling point of at least 150xc2x0 C. and a dielectric constant of at least 10 in the presence of a catalyst to form a compound of formula IVz 
f) alkylating a compound of the formula IVz 
with an alkylating agent of the formula XCH2R4az where X is a leaving group and R4az is xe2x80x94CO2R4b, where R4bz is an acid protecting group to form a compound of formula IIIz 
g) reacting a compound of formula IIIz 
with oxalyl chloride and ammonia to form a compound of formula IIz 
h) optionally hydrolyzing a compound of formula IIz 
to form a compound of formula Iz.
An alternative protocol useful for the synthesis of the starting material is shown in Scheme 1 below: 
The synthesis of indole-3-oxime amides (compound of formula I and II, supra.) of this invention uses as starting material the glyoxamide ((3(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid methyl ester, compound 10, supra. This starting material is prepared as set out in the preceding section or by the method of Example 9 of U.S. Pat. No. 5,654,326 (the disclosure of which is incorporated herein by reference).
To obtain the glyoxylamide starting material substituted in the 4-position with an (acidic group) linked through an oxygen atom, the reactions outlined in the scheme supra, are used (for conversions 1 through 5, see ref. Robin D. Clark, Joseph M. Muchowski, Lawrence E. Fisher, Lee A. Flippin, David B. Repke, Michel Souchet, Synthesis, 1991, 871-878, the disclosures of which are incorporated herein by reference). The starting material ortho-nitrotoluene, 1, is readily reduced to 2-methyl,3-methoxyaniline, 2. Reduction of lis by the catalytic hydrogenation of the corresponding nitrotoluene using palladium on carbon as catalyst. The reduction can be carried out in ethanol or tetrahydrofuran (THF) or a combination of both, using a low pressure of hydrogen. The aniline 2, obtained, is converted to the N-tert-butyloxycarbonyl derivative 3, in good yield, on heating with di-tert-butyl dicarbonate in THF at reflux temperature. The dilithium salt of the dianion of 3 is generated at xe2x88x9240 to xe2x88x9220xc2x0 C. in THF using sec-butyllithium and reacted with the appropriately substituted N-methoxy-N-methylalkanamide to form the ketone 4. This product (4) may be purified by crystallization from hexane, or reacted directly with trifluoroacetic acid in methylene chloride to give the 1,3-unsubstituted indole 5. The 1,3-unsubstituted indole 5 is reacted with sodium hydride in dimethylformamide at room temperature (20-25xc2x0 C.) for 0.5-1.0 hour. The resulting sodium salt of 5 is treated with an equivalent of arylmethyl halide and the mixture stirred at a temperature range of 0-100xc2x0 C., usually at ambient room temperature, for a period of 4 to 36 hours to give the 1-arylmethylindole, 6. This indole, 6, is O-demethylated by stirring with boron tribromide in methylene chloride for approximately 5 hours (see ref. Tsung-Ying Shem and Charles A Winter, Adv. Drug Res., 1977, 12, 176, the disclosure of which is incorporated herein by reference). The 4-hydroxyindole, 7, is alkylated with an alpha bromoalkanoic acid ester in dimethylformamide (DMF) using sodiumhydride as a base, with reaction condition of 5 to 6. The xcex1-[(indol-4-yl)oxy]alkanoic acid ester, 8, is reacted with oxalyl chloride in methylene chloride to give 9, which is not purified but reacted directly with ammonia to give the glyoxamide 10.
Glyoxamide starting material compounds substituted at the 5 position of the indole nucleus with an (acidic group) may be prepared by methods and starting materials shown in schemes 2 and 3 of U.S. Pat. No. 5,654,326; the disclosure of which is incorporated herein by reference.
IV. Methods of Using the Compounds of the Invention:
The indole compounds described herein are believed to achieve their beneficial therapeutic action principally by direct inhibition of mammalian (including human) sPLA2, and not by acting as antagonists for arachidonic acid, nor other active agents below arachidonic acid in the arachidonic acid cascade, such as 5-lipoxygenases, cyclooxygenases, and etc.
The method of the invention for inhibiting sPLA2 mediated release of fatty acids comprises contacting mammalian sPLA2 with an therapeutically effective amount of indole compounds corresponding to Formulae (I) or (II) as described herein including salt or a prodrug derivative thereof.
Another aspect of this invention is a method for treating Inflammatory Diseases such as inflammatory bowel disease, septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, osteoarthritis, and related diseases which comprises administering to a mammal (including a human) a therapeutically effective dose of the indole compound of the invention (see, formulae I and II).
As previously noted the compounds of this invention are useful for inhibiting sPLA2 mediated release of fatty acids such as arachidonic acid. By the term, xe2x80x9cinhibitingxe2x80x9d is meant the prevention or therapeutically significant reduction in release of sPLA2 initiated fatty acids by the compounds of the invention. By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a non-toxic dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an active compound of this invention.
Preferably compounds of the invention (per Formula I or II) or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of Active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration.
The compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the indole compound of the invention together with a pharmaceutically acceptable carrier or diluent therefor. The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.
In making the compositions of the present invention, the Active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointment, containing, for example, up to 10% by weight of the active compound. The compounds of the present invention are preferably formulated prior to administration.
For the pharmaceutical formulations any suitable carrier known in the art can be used. In such a formulation, the carrier may be a solid, liquid, or mixture of a solid and a liquid. For example, for intravenous injection the compounds of the invention may be dissolved in at a concentration of 2 mg/ml in a 4% dextrose/0.5% Na citrate aqueous solution. Solid form formulations include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc.
In powders the carrier is a finely divided solid which is in admixture with the finely divided Active ingredient. In tablets the Active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 1 to about 99 weight percent of the Active ingredient which is the novel compound of this invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter.
Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs.
The Active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The Active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol. Other compositions can be made by dispersing the finely divided Active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
The following pharmaceutical formulations 1 thru 8 are illustrative only and are not intended to limit the scope of the invention in any way. xe2x80x9cActive ingredientxe2x80x9d, refers to a compound according to Formula (I) or (II) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Hard gelatin capsules are prepared using the following ingredients:
A tablet is prepared using the ingredients below:
The components are blended and compressed to form tablets each weighing 665 mg
An aerosol solution is prepared containing the following components:
The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to xe2x88x9230xc2x0 C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
Tablets, each containing 60 mg of Active ingredient, are made as follows:
The Active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Capsules, each containing 80 mg of Active ingredient, are made as follows:
The Active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
Suppositories, each containing 225 mg of Active ingredient, are made as follows:
The Active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
Suspensions, each containing 50 mg of Active ingredient per 5 ml dose, are made as follows:
The Active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
An intravenous formulation may be prepared as follows:
The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.